EP1060673A1 - Method for increasing the production of propionate in the gastro-intestinal tract - Google Patents

Method for increasing the production of propionate in the gastro-intestinal tract Download PDF

Info

Publication number
EP1060673A1
EP1060673A1 EP99109916A EP99109916A EP1060673A1 EP 1060673 A1 EP1060673 A1 EP 1060673A1 EP 99109916 A EP99109916 A EP 99109916A EP 99109916 A EP99109916 A EP 99109916A EP 1060673 A1 EP1060673 A1 EP 1060673A1
Authority
EP
European Patent Office
Prior art keywords
dextran
nutritional composition
mammal
propionate
preparation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP99109916A
Other languages
German (de)
French (fr)
Other versions
EP1060673B1 (en
Inventor
Alfred Jann
Eva Arrigoni
Florence Rochat
Daniel Schmid
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Societe des Produits Nestle SA
Nestle SA
Original Assignee
Societe des Produits Nestle SA
Nestle SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=8238212&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=EP1060673(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Societe des Produits Nestle SA, Nestle SA filed Critical Societe des Produits Nestle SA
Priority to AT99109916T priority Critical patent/ATE270822T1/en
Priority to EP99109916A priority patent/EP1060673B1/en
Priority to DE69918680T priority patent/DE69918680T2/en
Priority to PCT/EP2000/004744 priority patent/WO2000070964A1/en
Priority to US09/979,533 priority patent/US7091194B1/en
Priority to NZ515196A priority patent/NZ515196A/en
Priority to AU59689/00A priority patent/AU772597B2/en
Priority to CA002374041A priority patent/CA2374041C/en
Publication of EP1060673A1 publication Critical patent/EP1060673A1/en
Priority to ZA200109013A priority patent/ZA200109013B/en
Publication of EP1060673B1 publication Critical patent/EP1060673B1/en
Application granted granted Critical
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/721—Dextrans
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
    • A23L29/20—Foods or foodstuffs containing additives; Preparation or treatment thereof containing gelling or thickening agents
    • A23L29/269—Foods or foodstuffs containing additives; Preparation or treatment thereof containing gelling or thickening agents of microbial origin, e.g. xanthan or dextran
    • A23L29/273—Dextran; Polysaccharides produced by leuconostoc
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/115—Fatty acids or derivatives thereof; Fats or oils
    • A23L33/12—Fatty acids or derivatives thereof
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/20—Reducing nutritive value; Dietetic products with reduced nutritive value
    • A23L33/21—Addition of substantially indigestible substances, e.g. dietary fibres

Definitions

  • This invention relates to a method for preferentially increasing the synthesis of propionate in the gastrointestinal tract by administering dextran.
  • the invention also relates to methods for the nutritional management of blood cholesterol levels, blood triglyceride levels, blood lipoprotein levels, and insulin sensitivity by administering dextran.
  • non-digestible polysaccharides which are often termed prebiotic fibres, are fermented by micro-organisms in the gastro-intestinal tract. Examples of these polysaccharides are inulin and its hydrolysis products. The products of the fermentation lead to the provision of energy, the selective stimulation of growth of lactic acid bacteria and the regulation of cellular metabolism.
  • One class of these fermentation products are the short chain fatty acids acetate, propionate and butyrate.
  • propionate is thought to (i) mediate the reduced hepatic gluconeogenesis induced by non-digestible polysaccharides, (ii) inhibit gluconeogenesis in the liver, (iii) enhance glycolysis, (iv) lower plasma fatty acid concentrations, (v) inhibit ureagenesis in the liver, and (v) increase insulin sensitivity ( Roberfroid et al; 1998; Annu. Rev. Nutr. ; 18:117-43). Acetate, however, increases plasma fatty acid concentrations (Roberfroid et al; 1998; Annu. Rev. Nutr.; 18:117-43).
  • this invention provides a method for selectively increasing the production of propionate in the gastro-intestinal tract, the method comprising enterally administering to a mammal a nutritional composition which contains dextran.
  • dextran when fermented by micro-organisms which occur in the gastro-intestinal tract, results in the increased production of propionate when compared to other non-digestible polysaccharides. Therefore, dextran is an ideal source of propionate in the gastro-intestinal tract.
  • extract means a group of polysaccharide which are composed of ⁇ -D-glucopyranosyl units linked predominantly ⁇ -D(1 ⁇ 6).
  • Dextrans are produced by certain types bacteria growing on a glucose substrate; for example Leuconostoc mesenteroides, Leuconostoc dextranicum, and Leuconostoc mesenteroides ssp. cremoris. Further, shorter chain dextrans may be obtained by hydrolysing native dextrans or by synthesising them.
  • this invention provides a method for decreasing blood cholesterol levels in a mammal, the method comprising enterally administering to a mammal a nutritional composition which contains dextran.
  • this invention provides a method for decreasing blood triglyceride levels in a mammal, the method comprising enterally administering to a mammal a nutritional composition which contains dextran.
  • this invention provides a method for decreasing very low density lipoprotein levels in a mammal, the method comprising enterally administering to a mammal a nutritional composition which contains dextran.
  • this invention provides a method for increasing high density lipoprotein levels in a mammal, the method comprising enterally administering to a mammal a nutritional composition which contains dextran.
  • this invention provides a method for increasing insulin sensitivity in a mammal, the method comprising enterally administering to a mammal a nutritional composition which contains dextran.
  • This invention is based upon the discovery that the colonic fermentation of dextran by micro-organisms results in the production of relatively larger amounts of propionate as compared to other non-digestible polysaccharides. Therefore, the enteral administration of dextran provides a convenient and simple way of selectively increasing the production of propionate in the gastro-intestinal tract.
  • the dextran used may be any suitable dextran; natural, synthetic or partially hydrolysed. Suitable dextrans are commercially available or may be produced by growing Leuconostoc micro-organisms on a sucrose substrate and isolating and purifying the dextran. Alternatively, the dextran may be produced as described in European patent application 0881283.
  • the dextran is a high molecular weight dextran; for example having a molecular weight above about 100000; for example above about 500000.
  • the dextran may be formulated into any suitable nutritional composition as desired since the exact composition and form is not critical.
  • One suitable class of nutritional compositions is food products. Examples of suitable food products include yoghurts, ice cream confections, milk-based drinks, salad dressings, sauces, toppings, desserts, confectionery products, biscuits, cereal-based snack bars, prepared dishes, and the like.
  • suitable food products include yoghurts, ice cream confections, milk-based drinks, salad dressings, sauces, toppings, desserts, confectionery products, biscuits, cereal-based snack bars, prepared dishes, and the like.
  • food products which are convenience foods are preferred since patient compliance is increased.
  • Another suitable class of nutritional compositions is nutritional formulas such as enteral formulas for clinical and infant nutrition, and nutritional supplements.
  • the nutritional compositions may be in the form of pet foods such as dried kibbles and retorted wet products.
  • the nutritional compositions may contain other ingredients as desired.
  • the nutritional compositions may contain other polysaccharides such as insoluble and soluble fibres. Fibres are known to have a beneficial effect upon cholesterol and glucose levels. Suitable sources of soluble and insoluble fibres are commercially available.
  • the inulin may be provided in the form of a natural extract which is suitable for human consumption.
  • Suitable inulin extracts may be obtained from Orafti SA of Tirlerront 3300, Belgium under the trade mark "Raftiline".
  • the inulin may be provided in the form of Raftiline®ST which is a fine white powder which contains about 90 to about 94% by weight of inulin, up to about 4% by weight of glucose and fructose, and about 4 to 9% by weight of sucrose.
  • the average degree of polymerisation of the inulin is about 10 to about 12.
  • the hydrolysis products of inulin are fructo-oligosaccharides in the form of fructose oligomers containing 1-kestose(GF2), nystose(GF3), and 1F-fructofuranosyl nystose(GF4), in which fructosyl units(F) are bound at the ⁇ -2,1 position of sucrose(GF) respectively.
  • the fructo-oligosaccharides may be obtained commercially, for example from Orafti SA of Tirlemont 3300, Belgium under the trade mark "Raftilose", or from Meiji Seika Co. of Japan.
  • the fructo-oligosaccharides may be provided in the form of Raftilose®P95.
  • Other oligosaccharides may be included if desired. Suitable examples are galacto-oligosaccarides, xylo-oligosaccharides or oligo derivatives of starch.
  • the ratio of soluble fibre to insoluble fibre is preferably about 1:3 to about 3:1; more preferably about 1:1 to about 2:1.
  • the nutritional composition may also contain vitamins and minerals as desired.
  • the nutritional composition preferably includes a complete vitamin and mineral profile.
  • sufficient vitamins and minerals may be provided to supply about 25% to about 250% of the recommended daily allowance of the vitamins and minerals per 1000 calories of the nutritional composition.
  • the nutritional composition when the nutritional composition is in the form of a food product or nutritional formula, the nutritional composition may contain a protein source, a lipid source and a carbohydrate source. These sources may be selected as desired.
  • the lipid source is preferably rich in monounsaturated fatty acids; for example monounsaturated fatty acids may provide at least 50% of energy of the lipid source.
  • the lipid source may also contain polyunsaturated fatty acids (omega-3 and omega-6 fatty acids).
  • the lipid profile is preferably designed to have a polyunsaturated fatty acid omega-6 (n-6) to omega-3 (n-3) ratio of about 4:1 to about 10:1.
  • Saturated fatty acids preferably provide less than 20% of the energy of the lipid source; for example less than about 15%.
  • the nutritional composition may be used in the nutritional management of conditions such as diabetes and hypercholesterolemia.
  • the amount of the nutritional composition required to be fed to a patient will vary depending upon factors such as the patient's condition, the patient's body weight, the age of the patient, and whether the nutritional composition is the sole source of nutrition. However the required amount may be readily set by a medical practitioner. In general, sufficient of the nutritional composition is administered to provide the patient with up to about 40 g of dietary fibre (insoluble and soluble) per day; for example about 25 g to about 35 g of dietary fibre per day. The amount of dextran that the patient receives is preferably in the range of about 2g to about 15g per day. If the nutritional formula is used as a supplement to other foods, the amount of the nutritional composition that is administered daily may be decreased accordingly.
  • the nutritional composition may be taken in multiple doses, for example 2 to 5 times, to make up the required daily amount or may taken in a single dose.
  • the nutritional composition may also be fed continuously over a desired period.
  • polysaccharides are fermented in an in vitro fermentation model which simulates fermentation conditions in the gastro-intestinal tract.
  • the polysaccharides are (i) acacia gum (available under the trade name Fibregum), (ii) Dextran produced according to European patent application 0881283, and (iii) lactulose.
  • a carbonate-phosphate buffer which contains oligo-elements, in a 50 ml air-tight flask.
  • the composition of the buffer is as follows:- Component Amount NaHCO 3 9.240g/l Na 2 HPO 4 . 12H 2 O 7.125g/l NaCl 0.470g/l KCl 0.450g/l Urea 0.400g/l CaCl 2 . 6H 2 O 0.108g/l Na 2 SO 4 0.100g/l MgCl 2 . 6H 2 O 0.100g/l FeSO 4 . 7H 2 O 36.80mg/l MnSO 4 .
  • Each flask is rinced for 1 minute with CO 2 gas and stored at 4°C for 16 hours under a slight over-pressure.
  • Dilute human faeces is prepared from samples of fresh faeces collected from healthy humans not having consumed antibiotics for at least 3 months and not producing methane.
  • the faeces are immediately rinced with CO 2 gas, and 3 parts (weight/weight) of the carbonate-phosphate buffer with oligo-elements are rapidly added at 37°C.
  • the mixture is blended for 2 minutes in a stomacher (Stomacher 400, Seward, London, GB) and filtered by a Polymon PES1000/45 filter with 1 mm holes (Schweizerische Seidenfabrik SA, Zürich,CH).
  • each flask is sealed air-tight and incubated in an agitated water bath at 37°C.
  • the content of short chain fatty acids in the flasks determined twice by direct injection of an acidified and sterile filtered sample on a gas chromatograph with FID (HP 8960, Hewlett Packard, Urdorf, CH) fitted with a DB-FFAP capillary column (MSP FRIEDLI & Co, Koeniz, CH).
  • mice were aged between 7 and 10 weeks. The mice are kept in sterile conditions in cages. The mice have free access to water and a standard diet.
  • mice On the first day of the study, each mouse is fed 0.5 ml of a complete human microbial flora, diluted 100 times, by intra-gastric tube. The feeding is repeated on day 2. On day 11, the mice are separated into three groups; each group being housed in a separate sterile isolation unit.
  • each group of mice receives a test diet.
  • the test diets are sterile.
  • the test diets all contain a potato puree, sugar, fish meal, cellulose, vitamins and minerals and a non-digestible polysaccharide.
  • the polysaccharides are as follows:- Diet Polysaccharide Positive Control Fructo-oligosaccharide (Raftilose) Negative Control Cellulose Diet 1 Dextran
  • mice are fed the diets until day 36. During this time, the development of the intestinal flora of each mouse is monitored by collecting faeces and determining microbial counts. A blood sample is collected from each mouse and analysed for short chain fatty acids. The mice are then anaesthetised and sacrificed. The caecum and stomach contents of each mouse is removed and analysed for short chain fatty acids and microbial flora, respectively.
  • mice fed Diet 1 have relatively higher levels of propionate in the blood and caecum.

Landscapes

  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Polymers & Plastics (AREA)
  • Nutrition Science (AREA)
  • Engineering & Computer Science (AREA)
  • Food Science & Technology (AREA)
  • Mycology (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Dispersion Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Plant Substances (AREA)

Abstract

A method for selectively increasing the production of propionate in the gastro-intestinal tract of a mammal. The method includes the step of enterally administering to the mammal a nutritional composition which contains dextran. Increasing the propionate production results in decreased blood cholesterol levels, decreased blood triglyceride levels, decreased very low density lipoprotein levels, increased high density lipoprotein levels, and increased insulin sensitivity.

Description

    Field of the invention
  • This invention relates to a method for preferentially increasing the synthesis of propionate in the gastrointestinal tract by administering dextran. The invention also relates to methods for the nutritional management of blood cholesterol levels, blood triglyceride levels, blood lipoprotein levels, and insulin sensitivity by administering dextran.
    • Background to the invention
  • Certain non-digestible polysaccharides, which are often termed prebiotic fibres, are fermented by micro-organisms in the gastro-intestinal tract. Examples of these polysaccharides are inulin and its hydrolysis products. The products of the fermentation lead to the provision of energy, the selective stimulation of growth of lactic acid bacteria and the regulation of cellular metabolism. One class of these fermentation products are the short chain fatty acids acetate, propionate and butyrate.
  • Of the short chain fatty acids, propionate is thought to (i) mediate the reduced hepatic gluconeogenesis induced by non-digestible polysaccharides, (ii) inhibit gluconeogenesis in the liver, (iii) enhance glycolysis, (iv) lower plasma fatty acid concentrations, (v) inhibit ureagenesis in the liver, and (v) increase insulin sensitivity (Roberfroid et al; 1998; Annu. Rev. Nutr.; 18:117-43). Acetate, however, increases plasma fatty acid concentrations (Roberfroid et al; 1998; Annu. Rev. Nutr.; 18:117-43).
  • The selective production of propionate in the gastro-intestinal tract would therefore be of benefit in the nutritional management of many conditions. However, the primary fatty acid which is produced upon fermentation of known non-digestible polysaccharides is acetate, followed by butyrate and propionate. Hence these non-digestible polysaccharides are not suitable for selectively increasing the production of propionate in the gastro-intestinal tract.
  • Therefore, it is an object of this invention to provide a method for selectively increasing the production of propionate in the gastro-intestinal tract.
    • Summary of the invention
  • Accordingly, in one aspect, this invention provides a method for selectively increasing the production of propionate in the gastro-intestinal tract, the method comprising enterally administering to a mammal a nutritional composition which contains dextran.
  • It has been surprisingly found that dextran, when fermented by micro-organisms which occur in the gastro-intestinal tract, results in the increased production of propionate when compared to other non-digestible polysaccharides. Therefore, dextran is an ideal source of propionate in the gastro-intestinal tract.
  • The term "dextran" means a group of polysaccharide which are composed of α-D-glucopyranosyl units linked predominantly α-D(1→6). Dextrans are produced by certain types bacteria growing on a glucose substrate; for example Leuconostoc mesenteroides, Leuconostoc dextranicum, and Leuconostoc mesenteroides ssp. cremoris. Further, shorter chain dextrans may be obtained by hydrolysing native dextrans or by synthesising them.
  • In another aspect, this invention provides a method for decreasing blood cholesterol levels in a mammal, the method comprising enterally administering to a mammal a nutritional composition which contains dextran.
  • In another aspect, this invention provides a method for decreasing blood triglyceride levels in a mammal, the method comprising enterally administering to a mammal a nutritional composition which contains dextran.
  • In another aspect, this invention provides a method for decreasing very low density lipoprotein levels in a mammal, the method comprising enterally administering to a mammal a nutritional composition which contains dextran.
  • In another aspect, this invention provides a method for increasing high density lipoprotein levels in a mammal, the method comprising enterally administering to a mammal a nutritional composition which contains dextran.
  • In another aspect, this invention provides a method for increasing insulin sensitivity in a mammal, the method comprising enterally administering to a mammal a nutritional composition which contains dextran.
    • Detailed Description of the Preferred Embodiments
  • Embodiments of the invention are now described, by way of example only.
  • This invention is based upon the discovery that the colonic fermentation of dextran by micro-organisms results in the production of relatively larger amounts of propionate as compared to other non-digestible polysaccharides. Therefore, the enteral administration of dextran provides a convenient and simple way of selectively increasing the production of propionate in the gastro-intestinal tract.
  • The dextran used may be any suitable dextran; natural, synthetic or partially hydrolysed. Suitable dextrans are commercially available or may be produced by growing Leuconostoc micro-organisms on a sucrose substrate and isolating and purifying the dextran. Alternatively, the dextran may be produced as described in European patent application 0881283.
  • Preferably, however, the dextran is a high molecular weight dextran; for example having a molecular weight above about 100000; for example above about 500000.
  • The dextran may be formulated into any suitable nutritional composition as desired since the exact composition and form is not critical. One suitable class of nutritional compositions is food products. Examples of suitable food products include yoghurts, ice cream confections, milk-based drinks, salad dressings, sauces, toppings, desserts, confectionery products, biscuits, cereal-based snack bars, prepared dishes, and the like. For humans, food products which are convenience foods are preferred since patient compliance is increased. Another suitable class of nutritional compositions is nutritional formulas such as enteral formulas for clinical and infant nutrition, and nutritional supplements. For pets, the nutritional compositions may be in the form of pet foods such as dried kibbles and retorted wet products.
  • The nutritional compositions may contain other ingredients as desired. For example, the nutritional compositions may contain other polysaccharides such as insoluble and soluble fibres. Fibres are known to have a beneficial effect upon cholesterol and glucose levels. Suitable sources of soluble and insoluble fibres are commercially available.
  • An example of a suitable fibre is inulin or its hydrolysis products. The inulin may be provided in the form of a natural extract which is suitable for human consumption. Suitable inulin extracts may be obtained from Orafti SA of Tirlerront 3300, Belgium under the trade mark "Raftiline". For example, the inulin may be provided in the form of Raftiline®ST which is a fine white powder which contains about 90 to about 94% by weight of inulin, up to about 4% by weight of glucose and fructose, and about 4 to 9% by weight of sucrose. The average degree of polymerisation of the inulin is about 10 to about 12. The hydrolysis products of inulin are fructo-oligosaccharides in the form of fructose oligomers containing 1-kestose(GF2), nystose(GF3), and 1F-fructofuranosyl nystose(GF4), in which fructosyl units(F) are bound at the β-2,1 position of sucrose(GF) respectively. The fructo-oligosaccharides may be obtained commercially, for example from Orafti SA of Tirlemont 3300, Belgium under the trade mark "Raftilose", or from Meiji Seika Co. of Japan. For example, the fructo-oligosaccharides may be provided in the form of Raftilose®P95. Other oligosaccharides may be included if desired. Suitable examples are galacto-oligosaccarides, xylo-oligosaccharides or oligo derivatives of starch.
  • If both soluble and insoluble fibre are used, the ratio of soluble fibre to insoluble fibre is preferably about 1:3 to about 3:1; more preferably about 1:1 to about 2:1.
  • The nutritional composition may also contain vitamins and minerals as desired. For clinical applications, the nutritional composition preferably includes a complete vitamin and mineral profile. For example, sufficient vitamins and minerals may be provided to supply about 25% to about 250% of the recommended daily allowance of the vitamins and minerals per 1000 calories of the nutritional composition.
  • When the nutritional composition is in the form of a food product or nutritional formula, the nutritional composition may contain a protein source, a lipid source and a carbohydrate source. These sources may be selected as desired.
  • The lipid source is preferably rich in monounsaturated fatty acids; for example monounsaturated fatty acids may provide at least 50% of energy of the lipid source. The lipid source may also contain polyunsaturated fatty acids (omega-3 and omega-6 fatty acids). The lipid profile is preferably designed to have a polyunsaturated fatty acid omega-6 (n-6) to omega-3 (n-3) ratio of about 4:1 to about 10:1. Saturated fatty acids preferably provide less than 20% of the energy of the lipid source; for example less than about 15%.
  • The nutritional composition may be used in the nutritional management of conditions such as diabetes and hypercholesterolemia.
  • The amount of the nutritional composition required to be fed to a patient will vary depending upon factors such as the patient's condition, the patient's body weight, the age of the patient, and whether the nutritional composition is the sole source of nutrition. However the required amount may be readily set by a medical practitioner. In general, sufficient of the nutritional composition is administered to provide the patient with up to about 40 g of dietary fibre (insoluble and soluble) per day; for example about 25 g to about 35 g of dietary fibre per day. The amount of dextran that the patient receives is preferably in the range of about 2g to about 15g per day. If the nutritional formula is used as a supplement to other foods, the amount of the nutritional composition that is administered daily may be decreased accordingly.
  • The nutritional composition may be taken in multiple doses, for example 2 to 5 times, to make up the required daily amount or may taken in a single dose. The nutritional composition may also be fed continuously over a desired period.
  • The invention is now further described with reference to the following specific examples.
    • Example 1
  • Three non-digestible polysaccharides are fermented in an in vitro fermentation model which simulates fermentation conditions in the gastro-intestinal tract. The polysaccharides are (i) acacia gum (available under the trade name Fibregum), (ii) Dextran produced according to European patent application 0881283, and (iii) lactulose.
  • For each polysaccharide, an amount of 100 mg of the polysaccharide is added to 8 ml of a carbonate-phosphate buffer, which contains oligo-elements, in a 50 ml air-tight flask. The composition of the buffer is as follows:-
    Component Amount
    NaHCO3 9.240g/l
    Na2HPO4. 12H2O 7.125g/l
    NaCl 0.470g/l
    KCl 0.450g/l
    Urea 0.400g/l
    CaCl2 .6H2O 0.108g/l
    Na2SO4 0.100g/l
    MgCl2 .6H2O 0.100g/l
    FeSO4 .7H2O 36.80mg/l
    MnSO4 .H2O 11.59mg/l
    ZnSO4 .7H2O 4.40mg/l
    CoCl2 .6H2O 1.20mg/l
    NiCl2 1.00mg/l
    CuSO4 .5H2O 0.98mg/l
    Mo7(NH4)6O24 .4H2O 0.17mg/l
    Resazurine 1.00mg/l
  • Each flask is rinced for 1 minute with CO2 gas and stored at 4°C for 16 hours under a slight over-pressure.
  • Dilute human faeces is prepared from samples of fresh faeces collected from healthy humans not having consumed antibiotics for at least 3 months and not producing methane. The faeces are immediately rinced with CO2 gas, and 3 parts (weight/weight) of the carbonate-phosphate buffer with oligo-elements are rapidly added at 37°C. The mixture is blended for 2 minutes in a stomacher (Stomacher 400, Seward, London, GB) and filtered by a Polymon PES1000/45 filter with 1 mm holes (Schweizerische Seidenfabrik SA, Zürich,CH).
  • An amount of 2 ml of the dilute faeces is added to each flask and the head space gas is replaced by a flux of temperate CO2 gas for 1 minute. After equilibration of the pressure, each flask is sealed air-tight and incubated in an agitated water bath at 37°C.
  • After 24 hours, the content of short chain fatty acids in the flasks determined twice by direct injection of an acidified and sterile filtered sample on a gas chromatograph with FID (HP 8960, Hewlett Packard, Urdorf, CH) fitted with a DB-FFAP capillary column (MSP FRIEDLI & Co, Koeniz, CH). The results are as follows:-
    Polysaccharide Short Chain fatty acid SCFA Content (µmol/100mg) SCFA % of total
    Fibregum Acetate 648.2 63.7
    Propionate 228.6 22.5
    Butyrate 107.1 10.5
    Dextran Acetate 415.0 46.3
    Propionate 363.5 40.6
    Butyrate 87.6 9.8
    Lactulose Acetate 909.2 74.6
    Propionate 111.7 9.2
    Butyrate 172.2 14.1
  • The results indicate that fermentation of dextran results in increased production of propionate; relatively and absolutely. For the other polysaccharides, only acetate was favoured.
    • Example 2
  • A study is undertaken with 45 mice aged between 7 and 10 weeks. The mice are kept in sterile conditions in cages. The mice have free access to water and a standard diet.
  • On the first day of the study, each mouse is fed 0.5 ml of a complete human microbial flora, diluted 100 times, by intra-gastric tube. The feeding is repeated on day 2. On day 11, the mice are separated into three groups; each group being housed in a separate sterile isolation unit.
  • On day 15, each group of mice receives a test diet. The test diets are sterile. The test diets all contain a potato puree, sugar, fish meal, cellulose, vitamins and minerals and a non-digestible polysaccharide. The polysaccharides are as follows:-
    Diet Polysaccharide
    Positive Control Fructo-oligosaccharide (Raftilose)
    Negative Control Cellulose
    Diet 1 Dextran
  • The mice are fed the diets until day 36. During this time, the development of the intestinal flora of each mouse is monitored by collecting faeces and determining microbial counts. A blood sample is collected from each mouse and analysed for short chain fatty acids. The mice are then anaesthetised and sacrificed. The caecum and stomach contents of each mouse is removed and analysed for short chain fatty acids and microbial flora, respectively.
  • All mice fed Diet 1 have relatively higher levels of propionate in the blood and caecum.

Claims (9)

  1. The use of dextran in the preparation of a nutritional composition for selectively increasing the production of propionate in the gastro-intestinal tract of a mammal.
  2. The use of dextran in the preparation of a nutritional composition for decreasing blood cholesterol levels in a mammal.
  3. The use of dextran in the preparation of a nutritional composition for decreasing blood triglyceride levels in a mammal.
  4. The use of dextran in the preparation of a nutritional composition for decreasing very low density lipoprotein levels in a mammal.
  5. The use of dextran in the preparation of a nutritional composition for increasing high density lipoprotein levels in a mammal.
  6. The use of dextran in the preparation of a nutritional composition for increasing insulin sensitivity in a mammal.
  7. The use according to any of claims 1 to 6 in which the dextran is a high molecular weight dextran having a molecular weight above about 500000.
  8. The use according to any of claims 1 to 7 in which the nutritional composition further comprises inulin, fructo-oligo saccharide, galacto-oligosaccarides, or xylo-oligosaccharides, or mixtures thereof.
  9. The use according to any of claims 1 to 8 in which the nutritional composition further comprises a lipid source which is rich in monounsaturated fatty acids and poor in saturated fatty acids.
EP99109916A 1999-05-20 1999-05-20 Method for increasing the production of propionate in the gastro-intestinal tract Expired - Lifetime EP1060673B1 (en)

Priority Applications (9)

Application Number Priority Date Filing Date Title
AT99109916T ATE270822T1 (en) 1999-05-20 1999-05-20 METHOD FOR INCREASE PROPIONATE PRODUCTION IN THE GASTROINTESTINAL TRACT
EP99109916A EP1060673B1 (en) 1999-05-20 1999-05-20 Method for increasing the production of propionate in the gastro-intestinal tract
DE69918680T DE69918680T2 (en) 1999-05-20 1999-05-20 Process for increasing propionate production in the gastrointestinal tract
AU59689/00A AU772597B2 (en) 1999-05-20 2000-05-19 Method for increasing propionate in the gastro-intestinal tract
US09/979,533 US7091194B1 (en) 1999-05-20 2000-05-19 Method for increasing the production of propionate in the gastrointestinal tract
NZ515196A NZ515196A (en) 1999-05-20 2000-05-19 Method for increasing propionate in the gastro- intestinal tract
PCT/EP2000/004744 WO2000070964A1 (en) 1999-05-20 2000-05-19 Method for increasing propionate in the gastro-intestinal tract
CA002374041A CA2374041C (en) 1999-05-20 2000-05-19 Method for increasing propionate in the gastro-intestinal tract
ZA200109013A ZA200109013B (en) 1999-05-20 2001-10-31 Method for increasing propionate in the gastro-intestinal tract.

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
EP99109916A EP1060673B1 (en) 1999-05-20 1999-05-20 Method for increasing the production of propionate in the gastro-intestinal tract

Publications (2)

Publication Number Publication Date
EP1060673A1 true EP1060673A1 (en) 2000-12-20
EP1060673B1 EP1060673B1 (en) 2004-07-14

Family

ID=8238212

Family Applications (1)

Application Number Title Priority Date Filing Date
EP99109916A Expired - Lifetime EP1060673B1 (en) 1999-05-20 1999-05-20 Method for increasing the production of propionate in the gastro-intestinal tract

Country Status (9)

Country Link
US (1) US7091194B1 (en)
EP (1) EP1060673B1 (en)
AT (1) ATE270822T1 (en)
AU (1) AU772597B2 (en)
CA (1) CA2374041C (en)
DE (1) DE69918680T2 (en)
NZ (1) NZ515196A (en)
WO (1) WO2000070964A1 (en)
ZA (1) ZA200109013B (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007011222A2 (en) * 2005-07-15 2007-01-25 Nederlandse Organisatie Voor Toegepast-Natuurwetenschappelijk Onderzoek Tno Cholesterol-lowering food additive
WO2008054193A1 (en) * 2006-11-02 2008-05-08 N.V. Nutricia Nutritional products that comprise saccharide oligomers

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11103542B2 (en) * 2002-03-13 2021-08-31 Kibow Biotech, Inc. Composition and method for maintaining healthy kidney function
GB0221184D0 (en) * 2002-09-13 2002-10-23 Cerestar Holding Bv Carbohydrate materials in food and drink compositions
US20040052915A1 (en) 2002-09-13 2004-03-18 Carlson Ting L. Use of low glycemic index sweeteners in food and beverage compositions
FR2844453B1 (en) 2002-09-13 2006-05-19 Agronomique Inst Nat Rech USE OF PRE-BIOTICS FOR PREVENTING THE INSTALLATION OF TYPE II DIABETES

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0153013A2 (en) * 1984-02-01 1985-08-28 FISONS plc Oral compositions containing dextran
JPS60190717A (en) * 1984-03-09 1985-09-28 Meito Sangyo Kk Agent and method for reducing lipid level
EP0382355A2 (en) * 1989-02-09 1990-08-16 Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo Growth promoting agent for bacteria containing pullulan and/or dextran
EP0881283A1 (en) * 1997-05-31 1998-12-02 Societe Des Produits Nestle S.A. Production of dextran

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2731349A (en) * 1953-07-22 1956-01-17 Ohio Commw Eng Co Edible container for ice cream and the like
US2790720A (en) * 1953-12-18 1957-04-30 Ohio Commw Eng Co Food preservation
US2893873A (en) * 1956-12-06 1959-07-07 Midland Chemical Company Fondants and the like
US2938799A (en) * 1958-09-03 1960-05-31 Ohio Commw Eng Co Dry pudding composition
JPS5137668B2 (en) * 1971-09-23 1976-10-16
IT1052819B (en) * 1975-12-12 1981-07-20 Fargal Pharmasint Lab Biochim DIETHYLAMIN ETHYL DEXTRANE-BASED LIPID ABSORPTION INHIBITOR PREPARATION

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0153013A2 (en) * 1984-02-01 1985-08-28 FISONS plc Oral compositions containing dextran
JPS60190717A (en) * 1984-03-09 1985-09-28 Meito Sangyo Kk Agent and method for reducing lipid level
EP0382355A2 (en) * 1989-02-09 1990-08-16 Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo Growth promoting agent for bacteria containing pullulan and/or dextran
EP0881283A1 (en) * 1997-05-31 1998-12-02 Societe Des Produits Nestle S.A. Production of dextran

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
D.MC CORMICK ET AL: "Annual Review of Nutrition", ANNUAL REVIEWS, PALO ALTO,CALIFORNIA,USA, XP002123057 *
D.SOUTHGATE ET AL.: "Dietary Fibre:Chemical and biological Aspects", 1990, ROYAL SOCIETY OF CHEMISTR, CAMBRIDGE,GB, XP002122986 *
PATENT ABSTRACTS OF JAPAN vol. 010, no. 043 (C - 329) 20 February 1986 (1986-02-20) *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007011222A2 (en) * 2005-07-15 2007-01-25 Nederlandse Organisatie Voor Toegepast-Natuurwetenschappelijk Onderzoek Tno Cholesterol-lowering food additive
WO2007011222A3 (en) * 2005-07-15 2007-03-08 Tno Cholesterol-lowering food additive
WO2008054193A1 (en) * 2006-11-02 2008-05-08 N.V. Nutricia Nutritional products that comprise saccharide oligomers
WO2008054211A1 (en) * 2006-11-02 2008-05-08 N.V. Nutricia Nutritional products comprising saccharide oligomers
RU2469557C2 (en) * 2006-11-02 2012-12-20 Н.В. Нютрисиа Use of galactooligosaccharides for increasing body insulin sensitivity

Also Published As

Publication number Publication date
AU5968900A (en) 2000-12-12
AU772597B2 (en) 2004-04-29
CA2374041A1 (en) 2000-11-30
DE69918680D1 (en) 2004-08-19
WO2000070964A1 (en) 2000-11-30
US7091194B1 (en) 2006-08-15
ZA200109013B (en) 2003-01-31
DE69918680T2 (en) 2005-07-28
NZ515196A (en) 2003-09-26
ATE270822T1 (en) 2004-07-15
EP1060673B1 (en) 2004-07-14
CA2374041C (en) 2005-11-29

Similar Documents

Publication Publication Date Title
KR100516532B1 (en) Inulin Products with Improved Nutritional Properties
US5792754A (en) Nutritional composition containing fibres
Velázquez et al. E¡ ect of Oligosaccharides and Fibre Substitutes on Short-chain Fatty Acid Production by Human Faecal Microflora
Causey et al. Effects of dietary inulin on serum lipids, blood glucose and the gastrointestinal environment in hypercholesterolemic men
Slavin et al. Partially hydrolyzed guar gum: clinical nutrition uses
CA2610711C (en) Use of polydextrose for simulating the functional attributes of human milk oligosaccharides in formula-fed infants
Boehm et al. Prebiotic carbohydrates in human milk and formulas
JP3937002B2 (en) Nutritional composition based on fiber
CN101951794B (en) Sphingo and Non-digestible carbohydrates improve the purposes of intestinal microbiota
JP2005513077A (en) Matrix-forming composition containing pectin
CN109619358A (en) A kind of solid drinks and preparation method thereof based on soybean peptide albumen powder
Scheppach et al. Addition of dietary fiber to liquid formula diets: the pros and cons
PT1255449E (en) Nutritional formulation containing prebiotic substances
TW200402300A (en) Use of pullulan as a slowly digested carbohydrate
DE60022513T2 (en) USE OF FATTY ACID DERIVATES IN NASAL GASTRALE ENTERAL FORMULATIONS
US20220248739A1 (en) Non-digestible oligosaccharides for decreased colonic protein fermentation
EP1060673B1 (en) Method for increasing the production of propionate in the gastro-intestinal tract
WO2008075793A1 (en) Composition for promoting bioabsorption of flavonoid, food/beverage for promoting bioabsorption of flavonoid using the composition, and method for production of the food/beverage
EP4346450A1 (en) Infant formula for feeding infants receiving infant formula and human breast milk
Juśkiewicz et al. The effect of the administration of cellulose and fructans with different degree of polymerization to rats on caecal fermentation and biochemical indicators in the serum
RU2816647C2 (en) Indigestible oligosaccharides for reduction of colonic fermentation of protein
Rochman et al. In Vitro Determination of Fe Levels and Fe Bioavaailabilities Prediction from Dahlia Tuber Syrup (Pinnata Cav.)
Caers The role of prebiotic fibres in the process of calcium absorption
Stewart et al. Fermentability of resistant starch preparations varies in vitro
Muhammad Saeed et al. Potential application of inulin in food industry; a review.

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LI LU NL PT SE

AX Request for extension of the european patent

Free format text: AL;LT;LV;MK;RO;SI

17P Request for examination filed

Effective date: 20010620

AKX Designation fees paid

Free format text: AT BE CH DE DK ES FI FR GB GR IE IT LI LU NL PT SE

17Q First examination report despatched

Effective date: 20030723

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAL Information related to payment of fee for publishing/printing deleted

Free format text: ORIGINAL CODE: EPIDOSDIGR3

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LI LU NL PT SE

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20040714

Ref country code: LI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20040714

Ref country code: IT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT;WARNING: LAPSES OF ITALIAN PATENTS WITH EFFECTIVE DATE BEFORE 2007 MAY HAVE OCCURRED AT ANY TIME BEFORE 2007. THE CORRECT EFFECTIVE DATE MAY BE DIFFERENT FROM THE ONE RECORDED.

Effective date: 20040714

Ref country code: FR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20040714

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20040714

Ref country code: CH

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20040714

Ref country code: BE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20040714

Ref country code: AT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20040714

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REF Corresponds to:

Ref document number: 69918680

Country of ref document: DE

Date of ref document: 20040819

Kind code of ref document: P

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20041014

Ref country code: GR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20041014

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20041014

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20041025

NLV1 Nl: lapsed or annulled due to failure to fulfill the requirements of art. 29p and 29m of the patents act
REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

PLAQ Examination of admissibility of opposition: information related to despatch of communication + time limit deleted

Free format text: ORIGINAL CODE: EPIDOSDOPE2

PLBQ Unpublished change to opponent data

Free format text: ORIGINAL CODE: EPIDOS OPPO

PLAQ Examination of admissibility of opposition: information related to despatch of communication + time limit deleted

Free format text: ORIGINAL CODE: EPIDOSDOPE2

PLAR Examination of admissibility of opposition: information related to receipt of reply deleted

Free format text: ORIGINAL CODE: EPIDOSDOPE4

PLBI Opposition filed

Free format text: ORIGINAL CODE: 0009260

PLBQ Unpublished change to opponent data

Free format text: ORIGINAL CODE: EPIDOS OPPO

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20050520

PLAX Notice of opposition and request to file observation + time limit sent

Free format text: ORIGINAL CODE: EPIDOSNOBS2

REG Reference to a national code

Ref country code: HK

Ref legal event code: GR

Ref document number: 1035301

Country of ref document: HK

26 Opposition filed

Opponent name: NUMICO RESEARCH B.V.

Effective date: 20050413

EN Fr: translation not filed
PLAF Information modified related to communication of a notice of opposition and request to file observations + time limit

Free format text: ORIGINAL CODE: EPIDOSCOBS2

PLAF Information modified related to communication of a notice of opposition and request to file observations + time limit

Free format text: ORIGINAL CODE: EPIDOSCOBS2

PLBB Reply of patent proprietor to notice(s) of opposition received

Free format text: ORIGINAL CODE: EPIDOSNOBS3

PLCK Communication despatched that opposition was rejected

Free format text: ORIGINAL CODE: EPIDOSNREJ1

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20041214

PLBN Opposition rejected

Free format text: ORIGINAL CODE: 0009273

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: OPPOSITION REJECTED

27O Opposition rejected

Effective date: 20070913

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: IE

Payment date: 20140512

Year of fee payment: 16

Ref country code: GB

Payment date: 20140514

Year of fee payment: 16

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 20140515

Year of fee payment: 16

REG Reference to a national code

Ref country code: DE

Ref legal event code: R119

Ref document number: 69918680

Country of ref document: DE

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20150520

REG Reference to a national code

Ref country code: IE

Ref legal event code: MM4A

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20151201

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20150520

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20150520